Medical use of fluorenone derivatives for treating and preventing brain and spinal injury

Abstract

Newly-created fluorenone drugs can be used to prevent, treat, or otherwise reduce damage to a brain or spinal cord following a medical crisis. These new drugs are markedly improved analogs of previously-known fluorenone compounds that were never commercialized or developed into medically useful treatments. The new analogs have the following structure:where X is a lower alkyl, substituted alkyl, or cycloalkyl group, R is selected from certain types of ether, ester, or amide groups, and Y1 and Y2 are halogen, hydrogen, or methyl. These new compounds can penetrate a blood-brain barrier and potently inhibit the unwanted release of excitotoxic neurotransmitters by astrocyte cells following an injury or insult to the brain or spinal cord. As an illustration, some of these new analogs were more than 30 times more potent than the previously known best compound in reducing aspartate release by stressed astrocytes. The new analogs also reduce swelling in astrocytes, thereby promoting proper blood flow through the brain and spinal cord following an injury or other crisis. These new analogs have been shown to work with very good efficacy in in vivo animal models of focal or global brain ischemia.

What is claimed is:  
     
       1. A method of treating a human patient who is suffering or at risk of central nervous system damage, comprising the step of administering to the patient a pharmaceutical composition which contains a neuroprotective amount of a compound of the formula:                    
       wherein X is selected from the group consisting of lower alkyl containing 1 to 3 carbon atoms; substituted lower alkyl; and lower cycloalkyl;  
       wherein R is a substituted alkyl group in which the substituents are selected from the group consisting of aryl and substituted aryl; and substituted or unsubstituted heterocyclic rings having 0 or 1 nitrogen atom and at least one double bond wherein the alkyl group is attached to a carbon atom of the heterocyclic ring; and  
       wherein Y 1  and Y 2  are each selected from the group consisting of halogen, hydrogen, and methyl.  
     
     
       2. The method of treating a human patient of claim  1 , wherein X is selected from the group consisting of propyl, hydroxyethyl, haloethyl, and cycloalkyl having less than 6 carbons. 
     
     
       3. The method of claim  1  wherein R is a heterocyclic-alkyl group. 
     
     
       4. The method of claim  3  wherein R is an oxazinyl-alkyl group. 
     
     
       5. The method according to claim  3  wherein the compound is selected from the group consisting of: 
       2-{[(5,6-dichloro-2,3,9,9a-tetrahydro-3-oxo-9a-propyl-1H-fluoren-7-yl)oxy]methyl}-tetrahydro-1,3-oxazine;  
       2-{[(5,6-dichloro-2,3,9,9a-tetrahydro-3-oxo-9a-propyl-1H-fluoren-7-yl)oxy]methyl}oxazoline;  
       2-{[(5,6-dichloro-2,3,9,9a-tetrahydro-3-oxo-9a-propyl-1H-fluoren-7-yl)oxy]methyl}thiazoline; and,  
       enantiomers and pharmaceutically acceptable salts thereof.  
     
     
       6. The method of claim  3  wherein R is a pyridyl-alkyl group. 
     
     
       7. The method according to claim  6  wherein the compound is selected from the group consisting of: 
       5,6-dichloro-9a-propyl-7-(2-pyridylmethoxy)-2,3,9,9a-tetrahydro-1H-fluoren-3-one; and,  
       5,6-dichloro-9a-propyl-7-(3-pyridylmethoxy)-2,3,9,9a-tetrahydro-1H-fluoren-3-one; and,  
       5,6-dichloro-9a-propyl-7-(4-pyridylmethoxy)-2,3,9,9a-tetrahydro-1H-fluoren-3-one; and,  
       enantiomers and pharmaceutically acceptable salts thereof.  
     
     
       8. The method according to claim  1  wherein R is a heterocyclicaralkyl group. 
     
     
       9. The method according to claim  8  wherein the compound is selected from the group consisting of: 
       5,6-dichloro-2,3,9,9a-tetrahydro-7-[4-(2-oxazolinyl)-phenylmethoxy]-9a-propyl-1H-fluoren-3-one; and,  
       5,6-dichloro-2,3,9,9a-tetrahydro-7-[3-(2-oxazolinyl)-phenylmethoxy]-9a-propyl-1H-fluoren-3-one; and,  
       5,6-dichloro-2,3,9,9a-tetrahydro-7-[2-(2-oxazolinyl)-phenylmethoxy]-9a-propyl-1H-fluoren-3-one; and,  
       pharmaceutically acceptable salts thereof.